Constitutive Expression of c-FLIP in Hodgkin and Reed-Sternberg Cells

Thomas, Roman K.; Kallenborn, A; Wickenhauser, Claudia; Schultze, Joachim L.; Draube, Andreas; Vockerodt, Martina; Ré, Daniel; Diehl, Volker; Wolf, Jürgen

doi:10.1016/s0002-9440(10)62578-3

Cited by 94 publications

(78 citation statements)

References 44 publications

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“…As inhibition of constitutive NF-kB activation is sufficient to trigger apoptosis of H-RS cells without stimulation of death receptor or cytotoxic agents, survival of H-RS cells appears to depend on a balance between anti-apoptotic and pro-apoptotic activities. In support of this notion, the present study confirmed the downregulation of c-FLIP and Bcl-xL, which are reported to be frequently expressed in H-RS cells upon blocking of NF-kB activity [21][22][23][24] (Figure 5c and d).…”

Section: Discussionsupporting

confidence: 89%

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IκBα independent induction of NF-κB and its inhibition by DHMEQ in Hodgkin/Reed-Sternberg cells

Watanabe

Dewan

Taira

et al. 2007

Laboratory Investigation

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Constitutive nuclear factor kB (NF-kB) activation characterizes Hodgkin/Reed-Sternberg (H-RS) cells. Blocking constitutive NF-kB has been shown to be a potential strategy to treat Hodgkin lymphoma (HL). Here, for the first time we show that although constitutive NF-kB level of H-RS cell lines is very high, topoisomerase inhibitors further enhance NF-kB activation through IkB kinase activation in not only H-RS cell lines with wild-type IkBa, but also in those with IkBa mutations and lacking wild-type IkBa. Thus, both constitutive and inducible NF-kB are potential targets to treat HL. We also present the data that indicate the involvement of IkBb in NF-kB induction by topoisomerase inhibitors. A new NF-kB inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ) inhibited constitutive NF-kB activity and induced apoptosis of H-RS cell lines. DHMEQ also inhibited the growth of H-RS cells without significant systemic toxicity in a NOD/SCID/gc null (NOG) mice model. DHMEQ and topoisomerase inhibitors revealed enhancement of apoptosis of H-RS cells by blocking inducible NFkB. Results of this study suggest that both constitutive and inducible NF-kB are molecular targets of DHMEQ in the treatment of HL. The results also indicate that IkBb is involved in NF-kB activation in H-RS cells and IkBb substitutes for IkBa in H-RS cells lacking wild-type IkBa.

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Section: Discussionsupporting

confidence: 89%

“…[21][22][23][24] Bcl-xL and c-FLIP antagonize mitochondrial and membranous caspase activities. 25 We next examined changes in their expression upon DHMEQ treatment by Northern blotting and immunohistochemistry.…”

Section: Dhmeq-induced Apoptosis Involves Activation Of Caspases 3 8mentioning

confidence: 99%

IκBα independent induction of NF-κB and its inhibition by DHMEQ in Hodgkin/Reed-Sternberg cells

Watanabe

Dewan

Taira

et al. 2007

Laboratory Investigation

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“…On the other hand, there is high constitutive expression of FLIP in Reed-Sternberg cells of Hodgkin's lymphomas; and some evidences suggest that it prevents FAS-induced apoptosis in these cells. 30,18 There are also evidences that FLIP may inhibit the extrinsic apoptotic pathway in carcinomas of the prostate, 17 the stomach, 19 and the urinary bladder, 20 and melanoma. 31 On the other hand, FLIP has also been shown to be expressed in ovarian cancer, 32 a gynecologic type of tumor very similar to endometrial carcinoma.…”

Section: Discussionmentioning

confidence: 99%

FLIP is frequently expressed in endometrial carcinoma and has a role in resistance to TRAIL-induced apoptosis

Dolcet

Llobet

Pallarés

et al. 2005

Laboratory Investigation

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The FLICE-inhibitory protein (FLIP) plays a key role in the regulation of apoptosis triggered by death ligands. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been shown to induce apoptosis in some types of tumor but not in others. To assess the possible role of FLIP in apoptosis resistance in endometrial carcinoma, we performed an immunohistochemical study on a tissue microarray composed of 95 endometrial carcinomas. We found positive signals in 43% of the cases, as well as a significant difference in FLIP expression between stage I and II tumors. Moreover, we observed that endometrial carcinoma cell lines Ishikawa and KLE did not undergo apoptosis after TRAIL treatment.

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“…Many tumors are resistant to Fas-and TRAIL-induced cell death through different molecular mechanisms (Wright et al, 1994). Some produce decoy receptors (DcRs) (Roth et al, 2001) some, such as colon cancer cells, express FasL to perform the so-called 'tumor counterattack' (Hahne et al, 1996;O'Connel et al, 1996) Thomas et al, 2002). The caspase-8 inhibitor FLIP (FLICE-Inhibitory Protein) has a caspase-like domain, but it lacks amino-acid residues that are critical for caspase activity.…”

Section: Introductionmentioning

confidence: 99%

FLIP overexpression inhibits death receptor-induced apoptosis in malignant mesothelial cells

Rippo¹,

Moretti²,

Vescovi³

et al. 2004

Oncogene

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Tumors have developed several forms of resistance to receptor-induced cell death. Here, we show that malignant mesothelial (MM) cell lines as well as primary MM cells and normal mesothelial (NM) cells express Fas and TNFrelated apoptosis-inducing ligand (TRAIL) receptors DR4 and DR5. We found that, although Fas expression levels are comparable, only MM cells are resistant to cell death. Furthermore, MM cells show resistance to TRAILinduced apoptosis. Caspase-8 (FLICE) is not activated by death receptors triggering in malignant cells whereas it is well activated by nonreceptor stimuli, such as UV radiation. We found that FLIP (FLICE-Inhibitory Protein) is constitutively expressed in all MM cell lines and is more expressed in primary MM cells than in NM cells. Knockdown of FLIP expression in MM cell lines, by a FLIPsiRNA, re-established the normal response to apoptosis induced by Fas or DR4/DR5, which was blocked by pretreatment with the caspase-8 inhibitor z-IETD-fmk. These results indicate that MM cells develop an intrinsic resistance to apoptosis induced by death receptors upregulating the expression of the antiapoptotic protein c-FLIP.

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Constitutive Expression of c-FLIP in Hodgkin and Reed-Sternberg Cells

Cited by 94 publications

References 44 publications

IκBα independent induction of NF-κB and its inhibition by DHMEQ in Hodgkin/Reed-Sternberg cells

IκBα independent induction of NF-κB and its inhibition by DHMEQ in Hodgkin/Reed-Sternberg cells

FLIP is frequently expressed in endometrial carcinoma and has a role in resistance to TRAIL-induced apoptosis

FLIP overexpression inhibits death receptor-induced apoptosis in malignant mesothelial cells

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